Updated RUNX1-specific variant curation rules
| ACMG/AMP criteria code . | RUNX1-specification version 1 . | ACMG/AMP criteria code . | RUNX1-specification version 2 . |
|---|---|---|---|
| PM1_supporting | Missense variant affecting an aa residue between aa residues 105 and 204 within the RHD | PM1_supporting | Missense variant affecting an aa residue between aa residues 89 and 204 within the RHD |
| PM2 | Variant must be completely absent from all population databases. The mean coverage of RUNX1 in the population database used should be at least 20× | PM2_supporting | Variant must be completely absent from all population databases. The mean coverage of RUNX1 in the population database used should be at least 20× Note: PM2 is downgraded to PM2_supporting in this version |
| PM4_supporting | In-frame deletion/insertion affecting residues 105-204 within the RHD | PM4_supporting | In-frame deletion/insertion affecting residues 89-204 within the RHD |
| PM5_supporting | Missense change at the same residue where a different missense change has previously been determined to be LP | PM5_supporting | Applicable for: 1. Missense change at the same residue where a different missense change has previously been determined to be LP 2. Nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.5) |
| PP3 | Applicable for: 1. Missense variants with a REVEL score >0.75 2. Missense or synonymous variants if the variant alters the last 3 bases of an exon preceding a donor splice site or the first 3 bases of an exon following a splice acceptor site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF-like) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site 3. Intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for splice donor sites or −3 to −5 for splice acceptor sites for which the predicted decrease in the score is at least 75% (measured by both MES and SSF-like) regardless of the predicted creation/presence of a putative cryptic splice site Note: PP3 cannot be applied for canonical splice site variants | PP3 | Applicable for: 1. Missense variants with a REVEL score ≥0.88 and/or a SpliceAI score ≥0.38 2. Synonymous and intronic variants with any splicing prediction in SpliceAI ≥0.38. Note: PP3 cannot be applied for canonical splice site variants or 5′/3′ UTR variants |
| BP4 | Applicable for missense variants if all the following apply: 1. REVEL score <0.15 2. MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10% 3. No putative cryptic splice sites are created Applicable for synonymous, intronic, and noncoding variants if MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10%, and no putative cryptic splice sites are created | BP4 | Applicable for: 1. Missense variants with a REVEL score ≤0.50 and SpliceAI score ≤0.20 2. Synonymous and intronic variants with any splicing prediction in SpliceAI score ≤0.20 |
| BP7 | Applicable for intronic/noncoding variants at or beyond positions +7/–21 for which MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10%, and no putative cryptic splice sites are created. Additionally requires that evolutionary conservation tools predict the nucleotide is not conserved (ie, phyloP score ≤0.1 or the variant allele is the reference nucleotide in 1 primate and/or 3 mammal species) | BP7 | Applicable for synonymous and intronic variants for which the SpliceAI score ≤0.20 AND evolutionary conservation tools predict the site is not highly conserved (ie, phyloP100way score in GRCh38/hg38 ≤2.0 and/or the variant allele is the reference nucleotide in 1 primate and/or 3 mammal species) Note: BP7 cannot be applied for 5′/3′ UTR variants |
| ACMG/AMP criteria code . | RUNX1-specification version 1 . | ACMG/AMP criteria code . | RUNX1-specification version 2 . |
|---|---|---|---|
| PM1_supporting | Missense variant affecting an aa residue between aa residues 105 and 204 within the RHD | PM1_supporting | Missense variant affecting an aa residue between aa residues 89 and 204 within the RHD |
| PM2 | Variant must be completely absent from all population databases. The mean coverage of RUNX1 in the population database used should be at least 20× | PM2_supporting | Variant must be completely absent from all population databases. The mean coverage of RUNX1 in the population database used should be at least 20× Note: PM2 is downgraded to PM2_supporting in this version |
| PM4_supporting | In-frame deletion/insertion affecting residues 105-204 within the RHD | PM4_supporting | In-frame deletion/insertion affecting residues 89-204 within the RHD |
| PM5_supporting | Missense change at the same residue where a different missense change has previously been determined to be LP | PM5_supporting | Applicable for: 1. Missense change at the same residue where a different missense change has previously been determined to be LP 2. Nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.5) |
| PP3 | Applicable for: 1. Missense variants with a REVEL score >0.75 2. Missense or synonymous variants if the variant alters the last 3 bases of an exon preceding a donor splice site or the first 3 bases of an exon following a splice acceptor site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF-like) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site 3. Intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for splice donor sites or −3 to −5 for splice acceptor sites for which the predicted decrease in the score is at least 75% (measured by both MES and SSF-like) regardless of the predicted creation/presence of a putative cryptic splice site Note: PP3 cannot be applied for canonical splice site variants | PP3 | Applicable for: 1. Missense variants with a REVEL score ≥0.88 and/or a SpliceAI score ≥0.38 2. Synonymous and intronic variants with any splicing prediction in SpliceAI ≥0.38. Note: PP3 cannot be applied for canonical splice site variants or 5′/3′ UTR variants |
| BP4 | Applicable for missense variants if all the following apply: 1. REVEL score <0.15 2. MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10% 3. No putative cryptic splice sites are created Applicable for synonymous, intronic, and noncoding variants if MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10%, and no putative cryptic splice sites are created | BP4 | Applicable for: 1. Missense variants with a REVEL score ≤0.50 and SpliceAI score ≤0.20 2. Synonymous and intronic variants with any splicing prediction in SpliceAI score ≤0.20 |
| BP7 | Applicable for intronic/noncoding variants at or beyond positions +7/–21 for which MES and SSF-like predict either an increase in the canonical splice site score or a decrease in the canonical splice site score by no more than 10%, and no putative cryptic splice sites are created. Additionally requires that evolutionary conservation tools predict the nucleotide is not conserved (ie, phyloP score ≤0.1 or the variant allele is the reference nucleotide in 1 primate and/or 3 mammal species) | BP7 | Applicable for synonymous and intronic variants for which the SpliceAI score ≤0.20 AND evolutionary conservation tools predict the site is not highly conserved (ie, phyloP100way score in GRCh38/hg38 ≤2.0 and/or the variant allele is the reference nucleotide in 1 primate and/or 3 mammal species) Note: BP7 cannot be applied for 5′/3′ UTR variants |
GRCh38/hg38, Genome Reference Consortium Human Build 38; MES, MaxEntScan; RHD, runt homology domain; SSF-like, splice site finder-like; UTR, untranslated region.